AU2014316682A1 - 1,2,4-oxadiazole derivatives as immunomodulators - Google Patents

Abstract

The present invention relates to 1,2,4-oxadiazole and 1,2,4-thiadiazole compounds as therapeutic agents capable of inhibiting the programmed cell death 1 (PD1) signaling pathway. The invention also refers to derivatives of the therapeutic agents. The invention also encompasses the use of the said therapeutic agents and 5 derivatives for treatment of disorders via immunopotentiation comprising inhibition of immunosuppressive signal induced due to PD-1, PD-L1, or PD-L2 and therapies using them.

Description

WO 2015/033299 PCT/IB2014/064279 1,2,4-OXADIAZOLE DERIVATIVES AS IMMUNOMODULATORS This application claims the benefit of Indian provisional application number 401 i/CHE/2013, filed on September 06, 2013; which hereby incorporated by reference. TECHNICAL FIELD The present invention relates to 1,2,4-oxadiazole and 1,2,4-thiadiazole 5 compounds and their derivatives therapeutically useful as immune modulators. The invention also relates to pharmaceutical compositions comprising the said 1,2,4 oxadiazole and 1,2,4-thiadiazole compounds and their derivatives as therapeutic agents. BACKGROUND OF THE INVENTION Programmed cell death-i (PD-1) is a member of the CD28 superfamily that 10 delivers negative signals upon interaction with its two ligands, PD-Li or PD-L2. PD-i and its ligands are broadly expressed and exert a wider range of immunoregulatory roles in T cells activation and tolerance compared with other CD28 members. PD-i and its ligands are involved in attenuating infectious immunity and tumor immunity, and facilitating chronic infection and tumor progression. The biological significance of PD-i 15 and its ligand suggests the therapeutic potential of manipulation of PD-I pathway against various human diseases (Ariel Pedoeem et al., Curr Top Microbiol Immunol. (2011); 350:17-37). T-cell activation and dysfunction relies on direct and modulated receptors. Based on their functional outcome, co-signaling molecules can be divided as co-stimulators and 20 co-inhibitors, which positively and negatively control the priming, growth, differentiation and functional maturation of a T-cell response (Li Shi, et al., Journal of Hematology & Oncology 2013, 6:74). Therapeutic antibodies that block the programmed cell death protein-i (PD-1) immune checkpoint pathway prevent T-cell down regulation and promote immune 25 responses against cancer. Several PD-I pathway inhibitors have shown robust activity in various phases of on-going clinical trials (RD Harvey, Clinical Pharmacology & Therapeutics (2014); 96 2, 214-223). Programmed death-i (PD-1) is a co-receptor that is expressed predominantly by T cells. The binding of PD-i to its ligands, PD-Li or PD-L2, is vital for the 30 physiological regulation of the immune system. A major functional role of the PD-i signaling pathway is the inhibition of self-reactive T cells, which serve to protect against autoimmune diseases. Elimination of the PD-i pathway can therefore result in the 1 WO 2015/033299 PCT/IB2014/064279 breakdown of immune tolerance that can ultimately lead to the development of pathogenic autoimmunity. Conversely, tumor cells can at times co-opt the PD-i pathway to escape from immunosurveillance mechanisms. Therefore, blockade of the PD-i pathway has become an attractive target in cancer therapy. Current approaches include 5 six agents that are either PD-i and PD-Li targeted neutralizing antibodies or fusion proteins. More than forty clinical trials are underway to better define the role of PD-i blockade in variety of tumor types (Hyun-Tak Jin et al., Clinical Immunology (Amsterdam, Netherlands) (2014), 153(i), 145-152). International applications WO 01/14557, WO 02/079499, WO 2002/086083, WO 10 03/042402, WO 2004/004771, WO 2004/056875, W02006121168, W02008156712, WO2010077634, WO2011066389, WO2014055897, W02014059173, W02014100079 and US patent US08735553 report PD-i or PD-Li inhibitory antibodies or fusion proteins. Further, International applications, W02011161699, W02012/168944, 15 W02013144704 and W02013132317 report peptides or peptidomimetic compounds which are capable of suppressing and/or inhibiting the programmed cell death I (PDi) signaling pathway. Still there is a need for more potent, better and/or selective immune modulators of PD-i pathway. The present invention provides 1,2,4-oxadiazole and 1,2,4-thiadiazole 20 compounds which are capable of suppressing and/or inhibiting the programmed cell death I (PDi) signaling pathway. SUMMARY OF INVENTION In accordance with the present invention, 1,2,4-oxadiazole and 1,2,4-thiadiazole compounds or a pharmaceutically acceptable salt or a stereoisomer thereof, provided 25 which are capable of suppressing and/or inhibiting the programmed cell death I (PDi) signaling pathway. In one aspect, the present invention provides a 1,2,4-oxadiazole and 1,2,4 thiadiazole compounds of formula (I): R1 R5 R 3

R

6 - HN - N R 2 H N Q R4/ 2 WO 2015/033299 PCT/IB2014/064279 wherein, Q is S or 0;

R

1 is side chain of an amino acid Ser or Thr, optionally substituted with alkyl or acyl; 5 R 2 is hydrogen or -CO-Aaa; Aaa is an amino acid residue Thr or Ser; wherein a C-terminus thereof is a free terminus, is amidated or is esterified;

R

3 is side chain of an amino acid selected from Asn, Asp, Gln or Glu; ----- is an optional bond; 10 R4 and R 5 independently are hydrogen or absent;

R

6 is selected from hydrogen, alkyl or acyl; or a pharmaceutically acceptable salt or a stereoisomer thereof. In a further aspect of the present invention, it relates to pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt 15 or a stereoisomer and processes for preparing thereof. In yet another aspect of the present invention, it provides use of 1,2,4-oxadiazole and 1,2,4-thiadiazole compounds of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, which are capable of suppressing and/or inhibiting the programmed cell death 1 (PD 1) signaling pathway. 20 DETAILED DESCRIPTION OF THE INVENTION The present invention provides 1,2,4-oxadiazole and 1,2,4-thiadiazole compounds as therapeutic agents useful for treatment of disorders via immunopotentiation comprising inhibition of immunosuppressive signal induced due to PD-1, PD-L1, or PD-L2 and therapies using them. 25 Each embodiment is provided by way of explanation of the invention, and not by way of limitation of the invention. In fact, it will be apparent to those skilled in the art that various modification and variations can be made in the present invention without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment can be used on another embodiment to yield a still 30 further embodiment. Thus it is intended that the present invention cover such modifications and variations as come within the scope of the appended claims and their equivalents. Other objects, features, and aspects of the present invention are disclosed in, or are obvious from, the following detailed description. It is to be understood by one of 3 WO 2015/033299 PCT/IB2014/064279 ordinary skill in the art that the present discussion is a description of exemplary embodiments only, and is not to be construed as limiting the broader aspects of the present invention. In one embodiment, the present invention relates to compounds of formula (I) 5 R1 R5 R3

R

6 HN N R 2 H N Q R4/ wherein, Q is S or 0;

R

1 is side chain of an amino acid Ser or Thr, optionally substituted with alkyl or 10 acyl;

R

2 is hydrogen or -CO-Aaa; Aaa is an amino acid residue Thr or Ser; wherein a C-terminus thereof is a free terminus, is amidated or is esterified;

R

3 is side chain of an amino acid selected from Asn, Asp, Gln or Glu; 15 ----- is an optional bond; R4 and R 5 independently are hydrogen or absent;

R

6 is selected from hydrogen, alkyl or acyl; or a pharmaceutically acceptable salt or a stereoisomer thereof. In yet another embodiment, the present invention provides compounds of formula 20 (IA) R1 R3 O N

H

2 N N Aaa N 0 (IA) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,

R

1 , R 3 and Aaa are same as defined in formula (I). In yet another further embodiment, the present invention provides compounds of 25 formula (IB) 4 WO 2015/033299 PCT/IB2014/064279 R1 R3 N

H

2 N

NH

2 N-0 (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,

R

1 and R 3 are same as defined in formula (I). According to yet another embodiment, the present invention provides compounds 5 of the formula (I) in which

R

1 is side chain of Ser or Thr;

R

2 is -CO-Aaa; Aaa is an amino acid residue Thr or Ser; wherein the C-terminus is free;

R

3 is side chain of Asn or Glu. 10 In yet another further embodiment, the compound according to formula (I) in which Q is S. In yet another further embodiment, the compound according to formula (I) in which R 4 is hydrogen. In yet another further embodiment, the compound according to formula (I) in 15 which R 5 is hydrogen. The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. According to one embodiment, specifically provided are compounds of the formula (I), (IA) and (IB) in which R 1 is side chain of Ser. 20 According to another embodiment, specifically provided are compounds of the formula (I), (IA) and (IB) in which R 1 is side chain of Thr. According to yet another embodiment, specifically provided are compounds of the formula (I) in which R 2 is hydrogen. According to yet another embodiment, specifically provided are compounds of 25 the formula (I) in which R 2 is -CO-Aaa. According to yet another embodiment, specifically provided are compounds of the formula (I) and (IA) in which Aaa is Thr. According to yet another embodiment, specifically provided are compounds of the formula (I) and (IA) in which Aaa is Ser. 5 WO 2015/033299 PCT/IB2014/064279 According to yet another embodiment, specifically provided are compounds of the formula (I), (IA) and (IB) in which R 3 is side chain of Asn. According to yet another embodiment, specifically provided are compounds of the formula (I) and (IA) in which R 3 is side chain of Asp. 5 According to yet another embodiment, specifically provided are compounds of the formula (I) and (IA) in which R 3 is side chain of Gln. According to yet another embodiment, specifically provided are compounds of the formula (I) and (IA) in which R 3 is side chain of Glu. According to yet another embodiment, specifically provided are compounds of 10 the formula (I) in which Q is 0. According to yet another embodiment, specifically provided are compounds of the formula (I) in which R 1 is side chain of Ser, optionally substituted with C 1 5 alkyl such as methyl. According to yet another embodiment, specifically provided are compounds of 15 the formula (I) in which R 6 is hydrogen. According to yet another embodiment, specifically provided are compounds of the formula (I) in which R 6 is acyl such as -C(O)CH 3 , -C(O)CH 2

CH

3 , -C(O)(CH 2

)

2

CH

3 , C(O)(CH 2

)

3

CH

3 , -C(O)(CH 2

)

4

CH

3 or -C(O)(CH 2

)

5

CH

3 . According to yet another embodiment, specifically provided are compounds of 2 0 the formula (I) in which R 6 is butyryl. According to yet another embodiment, specifically provided are compounds of the formula (I) in which R 4 and R 5 are absent. According to yet another embodiment, specifically provided are compounds of the formula (I) in which C-terminus of Aaa is free (e.g. -CO 2 H form). 25 According to yet another embodiment, specifically provided are compounds of the formula (I) in which in which C-terminus of Aaa is esterified (e.g. -CO 2 Me form). According to yet another embodiment, specifically provided are compounds of the formula (I) in which C-terminus of Aaa is amidated (e.g. -CONH 2 form). According to yet another embodiment, specifically provided are compounds of 30 the formula (I), (IA) and (IB) in which one, more or all amino acid/s is/are D amino acid/s. In an embodiment, specific compounds of formula (I) without any limitation are enumerated in table (1): 6 WO 2015/033299 PCT/IB2014/064279 Table 1 Comp Comp ound Structure ound Structure No. No.

NH

2 14.

NH

2 HO HO O _ O OH

H

2 N N NH 2 H N OH N-0 N-O 0 2. NH 2 15. NH 2 HO O O OH HO" ',OH

H

2 N N OH

H

2 N N N H OH H N -Y N-O 0 N-O 0 3. NH 2 16. NH 2 HO,- O HO _ OH

H

2 N N NH 2

H

2 N N N HIOH N-O N-O 0 4. NH 2 17. NH 2 5. NH2 18. NH2 HO OH HO O OfOH _0 0 - ,O y Y

H

2 N N A O NN N OH 6. NH 2 19. O N H H N NN N OH N-O 0 N 0 H 7. NH2 20. 0 NH2 HO NNH O HO 0OH HO OH HNJ N' N N Oi NH ~ OH

H

2 N N OH H 2 N N N N 0 N HN-O H H HO -OOH -O OH N-0 0 N-0 0 7 WO 2015/033299 PCT/IB2014/064279 9. 22. O NH 2

NH

2 1 SOH OH HO OH OHH2 N N OH H N-0H H0H 2 N N N H H 0 10. NH 2 23. O NH 2 N O O OH HO N ' OH

H

2 N N k OH N OH H2 H N ( H I ~' N 0Nf N-- -O H H 11. NH 2 24. OH HO OH HO O O OH N OH H N OH

H

2 N *- N N1 H 2 N - N N I H HiI Yi H H N-O 0 N-0 and 12. NH 2 25. OH HO 0 OH HO O OH 7 OH

H

2 N N OH H2N N OH NV H I N N f N-O 0 N-0 0 13. NH 2 HO OH H2N N: N N O HN -O H H N-0 0 or a pharmaceutically acceptable salt or a stereoisomer thereof. In one embodiment, the present invention provides a pharmaceutical composition comprising the compound as disclosed, and a pharmaceutically acceptable carrier or diluent. 5 In another embodiment, the said pharmaceutical composition further comprising at least one of an anticancer agent, chemotherapy agent, or antiproliferative compound. The compounds as disclosed in the present invention are formulated for pharmaceutical administration. In one embodiment, the present invention provides compounds as disclosed in the 10 present invention for use in the preparation of a medicament. In another embodiment, the present invention provides compounds as disclosed in the present invention for use in the preparation of a medicament for the treatment of cancer or infectious disease. In one embodiment, the present invention provides compounds as disclosed in the 15 present invention for use in the preparation of a medicament for the treatment of bacterial infectious disease, a viral infectious disease or a fungal infectious disease. 8 WO 2015/033299 PCT/IB2014/064279 In one embodiment, the present invention provides compounds for use in the preparation of a medicament for the treatment of cancer wherein the cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, melanoma, prostate cancer and renal cancer, bone cancer, cancer of the head or neck, pancreatic 5 cancer, skin cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small 10 intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumours of childhood, lymphocytic lymphoma, cancer of the bladder, 15 cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. 20 In one embodiment, the present invention provides the compounds as disclosed in the present invention for use in the treatment of cancer. In one embodiment, the present invention provides the compounds as disclosed in the present invention for use in the treatment of bacterial infectious disease, a viral infectious disease or a fungal infectious disease. 25 In one embodiment, the present invention provides a method of treatment of cancer, wherein the method comprises administration of an effective amount of the compound of the present invention to the subject in need thereof. In another embodiment the present invention provides a method of modulating an immune response mediated by PD-i signaling pathway in a subject, comprising 30 administering to the subject a therapeutically effective amount of the compound of the present invention such that the immune response in the subject is modulated. In yet another embodiment the present invention provides a method of inhibiting growth of tumour cells and/or metastasis in a subject, comprising administering to the 9 WO 2015/033299 PCT/IB2014/064279 subject a therapeutically effective amount of compound of the present invention capable of inhibiting the programmed cell death 1 (PD1) signaling pathway. The said tumour cells include cancer such as but not limited to bone cancer, cancer of the head or neck, pancreatic cancer, skin cancer, cutaneous or intraocular 5 malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the 10 thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumours of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal 15 pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. In yet another further embodiment the present invention provides a method of 20 treating an infectious disease in a subject comprising administering to the subject a therapeutically effective amount of the compound of the present invention capable of inhibiting the programmed cell death 1 (PD1) signaling pathway such that the subject is treated for the infectious disease. Still yet another embodiment of the present invention provides a method of 25 treating bacterial, viral and fungal infections in a subject comprising administering to the subject a therapeutically effective amount of the compound of the present invention capable of inhibiting the programmed cell death 1 (PD 1) signaling pathway such that the subject is treated for the bacterial, viral and fungal infections. The infectious disease includes but not limited to HIV, Influenza, Herpes, 30 Giardia, Malaria, Leishmania, the pathogenic infection by the virus Hepatitis (A, B, & C), herpes virus (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella 10 WO 2015/033299 PCT/IB2014/064279 virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus, pathogenic infection by the bacteria chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, 5 pseudomonas, E. coli, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria, pathogenic infection by the fungi Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus fumigatuss, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, 10 Coccidioides immitis and Histoplasma capsulatum, and pathogenic infection by the parasites Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylus brasiliensis. 15 The compounds of the present invention may be used as single drugs or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials. The pharmaceutical composition is usually administered by oral or inhalation routes, but can be administered by parenteral administration route. In the practice of this 20 invention, compositions can be administered, for example, by orally, intravenous infusion, topically, intraperitoneally, intravesically or intrathecally. Examples of the parenteral administration includes but not limited to intraarticular (in the joints), intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain 25 antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Oral administration, parenteral administration, subcutaneous administration and intravenous administration are the preferred methods of 30 administration. The dosage of the compounds of the present invention varies depending on age, weight, symptom, therapeutic efficacy, dosing regimen and/or treatment time. Generally, they may be administered by oral or inhalation routes, in an amount of 1 mg to 100 mg 11 WO 2015/033299 PCT/IB2014/064279 per time, from once a couple of days, once 3 days, once 2 days, once a day to a couple of times a day, in the case of an adult, or continuously administered by oral or inhalation routes from 1 to 24 hours a day. Since the dosage is affected by various conditions, an amount less than the above dosage may sometimes work well enough, or higher dosage 5 may be required in some cases. The compounds of the present invention may be administered in combination with other drugs for (1) complementation and/or enhancement of prevention and/or therapeutic efficacy of the preventive and/or therapeutic drug of the present invention, (2) dynamics, absorption improvement, dosage reduction of the preventive and/or 10 therapeutic drug of the present invention, and/or (3) reduction of the side effects of the preventive and/or therapeutic drug of the present invention. A concomitant medicine comprising the compounds of the present invention and other drug may be administered as a combination preparation in which both components are contained in a single formulation, or administered as separate formulations. The 15 administration by separate formulations includes simultaneous administration and administration with some time intervals. In the case of the administration with some time intervals, the compound of the present invention can be administered first, followed by another drug or another drug can be administered first, followed by the compound of the present invention. The administration method of the respective drugs may be the same or 20 different. The dosage of the other drug can be properly selected, based on a dosage that has been clinically used. The compounding ratio of the compound of the present invention and the other drug can be properly selected according to age and weight of a subject to be administered, administration method, administration time, disorder to be treated, 25 symptom and combination thereof. For example, the other drug may be used in an amount of 0.01 to 100 parts by mass, based on 1 part by mass of the compound of the present invention. The other drug may be a combination of two or more kind of arbitrary drugs in a proper proportion. The other drug that complements and/or enhances the preventive and/or therapeutic efficacy of the compound of the present invention includes 30 not only those that have already been discovered, but those that will be discovered in future, based on the above mechanism. Diseases on which this concomitant use exerts a preventive and/or therapeutic effect are not particularly limited. The concomitant medicine can be used for any 12 WO 2015/033299 PCT/IB2014/064279 diseases, as long as it complements and/or enhances the preventive and/or therapeutic efficacy of the compound of the present invention. The compound of the present invention can be used with an existing chemotherapeutic concomitantly or in a mixture form. Examples of the chemotherapeutic 5 include an alkylation agent, nitrosourea agent, antimetabolite, anticancer antibiotics, vegetable-origin alkaloid, topoisomerase inhibitor, hormone drug, hormone antagonist, aromatase inhibitor, P-glycoprotein inhibitor, platinum complex derivative, other immunotherapeutic drugs and other anticancer drugs. Further, it can be used with a cancer treatment adjunct, such as a leucopenia (neutropenia) treatment drug, 10 thrombocytopenia treatment drug, antiemetic and cancer pain intervention drug, concomitantly or in a mixture form. In one embodiment, the compound(s) of the present invention can be used with other immunomodulators and/or a potentiating agent concomitantly or in a mixture form. Examples of the immunomodulator include various cytokines, vaccines and adjuvants. 15 Examples of these cytokines, vaccines and adjuvants that stimulates immune responses include but not limited to GM-CSF, M-CSF, G-CSF, interferon-aX, J, or y, IL-I, IL-2, IL 3 , IL-12, Poly (I:C) and CpG. In another embodiment, the potentiating agents includes cyclophosphamide and analogs of cyclophosphamide, anti-TGF and Imatinib (Gleevac), a mitosis inhibitor, 20 such as paclitaxel, Sunitinib (Sutent) or other antiangiogenic agents, an aromatase inhibitor, such as letrozole, an A2a adenosine receptor (A2AR) antagonist, an angiogenesis inhibitor, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists, and IL-18 antagonists. Unless defined otherwise, all technical and scientific terms used herein have the 25 same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention. As used herein, the term 'compound(s)' refers to the compounds disclosed in the present invention. 30 As used herein, the term "comprise" or "comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components. 13 WO 2015/033299 PCT/IB2014/064279 As used herein, the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting. As used herein, the term "optionally substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent 5 including, but not limited to: alkyl, alkoxy, acyl, halo, and hydroxyl. It is understood that the substituent may be further substituted. As used herein the term "alkyl" refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to twenty carbon atoms (i.e., C1-2o alkyl) or one to ten carbon atoms 10 (i.e., C1_1o alkyl) or one to five carbon atoms (i.e., C1_5 alkyl) and which is attached to the rest of the molecule by a single bond, e.g., including but not limited to methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl or neopentyl. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted. 15 As used herein, the term "acyl" refers to RC(O)-, wherein R is alkyl as defined above. Examples of acyl group include, but are not limited to acetyl, -C(O)(CH 2

)

4

CH

3 , C(O)(CH 2

)

6

CH

3 and -C(O)(CH 2

)

8

CH

3 . As used herein, the term "amidated C-terminus" refers to that the C-terminal of the amino acid in amide form. 20 As used herein, the term "amide form" refers to primary, secondary and/or tertiary amides and may be represented by the formula -C(O)NRxRy, wherein each of Rx and Ry independently represents hydrogen or alkyl. As used herein, the term "amino" refers to -NH 2 group. Unless set forth or recited to the contrary, all amino groups described or claimed herein may be substituted or 25 unsubstituted. As used herein, the term "amino acid" refers to amino acids having L or D stereochemistry at the alpha carbon. Optional substituent on amino acid means replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent, in case of amino acid containing hydroxyl group such as Serine or 30 Threonine, the hydroxyl group can be substituted with the specified substituent. As used herein, the term "aryl" refers to C 4

-C

1 0 carbocyclic aromatic system containing one or two rings wherein such rings may be fused. Examples of aryl groups include, but are not limited to phenyl and naphthyl. 14 WO 2015/033299 PCT/IB2014/064279 As used herein, the term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group (e.g., benzyl and the like). As used herein, the term "carboxylic acid" refers to -COOH group. As used herein, the term "coupling agent" means a compound that reacts with the 5 hydroxyl moiety of a carboxy moiety thereby rendering it susceptible to nucleophilic attack. Coupling agents of this type are known in the art and include, but are not limited to, EDCI, HATU, HOBt, DIC and DCC. As used herein the term "ester" refers to (C 1

-C

6 ) linear or branched alkyl, (C 4 Cio)aryl, (C 4 -Cio)heteroaryl or arylalkyl esters. 10 As used herein the term "esterified C-terminus" refers to that the C-terminal of the amino acid in ester form. As used herein the term "free C-terminus' refers to that the C-terminal of the amino acid in -CO2H form. As used herein, the terms "halogen" or "halo" includes fluorine, chlorine, 15 bromine or iodine. As used herein the term "Hydroxy" or "Hydroxyl" refers to -OH group. "Pharmaceutically acceptable salt" is taken to mean an active ingredient, which comprises a compound of the formula (I) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient 20 compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its 25 therapeutic efficacy in the body. "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use. 30 The term "stereoisomer/stereoisomers" refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds of formula (I), wherever they are chiral or when they bear one or more double bond. When the compounds of the formula (I) and related formulae are chiral, they can exist in racemic or in optically 15 WO 2015/033299 PCT/IB2014/064279 active form. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person 5 skilled in the art or even employed as such in the synthesis. In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N 10 benzoylproline or N-benzenesulfonylproline), or the various optically active camphorsulfonic acids. Also advantageous is chromatographic enantiomer resolution with the aid of an optically active resolving agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatised methacrylate polymers immobilised on silica gel). 15 The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non domestic animals (such as wildlife). The phrase "therapeutically effective amount" or "efficient amount" refers to sufficient amount of the compound(s) of the present invention that (i) treats or prevents 20 the particular disease, disorder or syndrome (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, disorder or syndrome or (iii) prevents or delays the onset of one or more symptoms of the particular disease, disorder or syndrome described herein. In the case of cancer, the therapeutically effective amount of the drug may decrease the number of cancer cells; decrease the cancer size; inhibit (i.e., slow to 25 some extent and alternatively stop) cancer cell infiltration into peripheral organs; suppress (i.e., slow to some extent and alternatively stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. In the case of infectious disease states, the therapeutic effective amount is an amount sufficient to decrease or alleviate an infectious diseases, 30 the symptoms of an infections caused by bacterial, viral and fungal. Naturally-occurring amino acids are identified throughout the specification by the conventional three-letter abbreviations indicated in the below table 2: Table 2 (Amino acid codes) 16 WO 2015/033299 PCT/IB2014/064279 Name 3-letter code Name 3-letter code Asparagine Asn Glutamine Gin Aspartic acid Asp Serine Ser Glutamic acid Glu Threonine Thr The abbreviations used in the entire specification may be summarized herein below with their particular meaning. C (degree Celsius); 6 (delta); % (percentage); brine (NaCl solution); CDI 5 CH 2 Cl 2 /DCM (Dichloromethane); DMF (Dimethyl formamide); DMSO (Dimethyl sulphoxide); DCC (Dicyclohexylcarbodiimide); DIC (N,N'-diisopropylcarbodiimide); DMSO-d 6 (Deuterated DMSO); EDC.HCI/EDCI (1-(3-Dimethyl aminopropyl)-3 carbodiimide hydrochloride); Et 2 NH (Diethyl amine); EtOH (Ethanol); EtOAc (Ethyl acetate); ECF (ethylchloroformate); Fmoc (Fluorenylmethyloxycarbonyl chloride); g or 10 gr (gram); H or H 2 (Hydrogen); H 2 0 (Water); HOBt/HOBT (1-Hydroxy benzotriazole); HCl (Hydrochloric acid); h or hr (Hours); HATU (2-(1H-7-Azabenzotriazol-1-yl) 1,1,3,3-tetramethyl uranium hexafluoro phosphate methanaminium); Hz (Hertz); HPLC (High-performance liquid chromatography); K 2

CO

3 (Potassium carbonate); LiOH (Lithium hydroxide); LCMS (Liquid chromatography mass spectroscopy); mmol 15 (Millimoles); M (Molar); pl (Micro litre); mL (Millilitre); mg (Milligram); m (Multiplet); MHz (Megahertz); MS (ES) (Mass spectroscopy-electro spray); min. (Minutes); Na (Sodium); NaHCO 3 (Sodium bicarbonate); NaOAc (Sodium acetate); NMM (N-methyl morpholine); Na 2

SO

4 (Sodium sulphate); N 2 (Nitrogen); NMR (Nuclear magnetic resonance spectroscopy); NH 3 (Ammonia); NH 2 OH.HCl (Hydroxylamine 20 hydrochloride; PD-Li (Programmed death-ligand 1); PD-L2 (Programmed cell death 1 ligand 2); prep-HPLC/preparative HPLC (Preparative High-performance liquid chromatography); S (Singlet); t Bu (tertiary butyl); TEA/Et 3 N (Triethyl amine); TFA (Trifluoroaceticacid); TFAA (Trifluroacetic anhydride); TLC (Thin Layer Chromatography); THF (Tetrahydrofuran); TIPS (Triisopropylsilane); TFA/CF 3 COOH 25 (Trifluoroacetic acid); t (Triplet); tR = (Retention time); Trt (Triphenyl methane); etc. EXPERIMENTAL An embodiment of the present invention provides the preparation of compounds of formula (I) according to the procedures of the following examples, using appropriate materials. Those skilled in the art will understand that known variations of the conditions 17 WO 2015/033299 PCT/IB2014/064279 and processes of the following preparative procedures can be used to prepare these compounds. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present invention. The starting materials are generally available from commercial sources such as 5 Sigma-Aldrich, USA or Germany; Chem-Impex USA; G.L. Biochem, China and Spectrochem, India. Purification and characterization of compounds Analytical HPLC method: Analytical HPLC was performed using on ZIC HILIC 200 A' column (4.6 mm x 250 mm, 5 p m), Flow rate: 1.0 mL / min. The elution 10 conditions used are: Buffer A: 5 mmol ammonium acetate, Buffer B: Acetonitrile, Equilibration of the column with 90 % buffer B and elution by a gradient of 90 % to 40 % buffer B during 30 min. Preparative HPLC Method: Preparative HPLC was performed using on SeQuant ZIC HILIC 200 A' column (10 mm x 250 mm, 5 pm), Flow rate: 5.0 mL/min. 15 The elution conditions used are: Buffer A: 5 mmol ammonium acetate (adjust to pH-4 with Acetic Acid), Buffer B: Acetonitrile, Equilibration of the column with 90 % buffer B and elution by a gradient of 90 % to 40 % buffer B during 20 min.. LCMS was performed on API 2000 LC/MS/MS triple quad (Applied bio systems) with Agilent 1100 series HPLC with G1315 B DAD, using Mercury MS 20 column or using Agilent LC/MSD VL single quad with Agilent 1100 series HPLC with G1315 B DAD, using Mercury MS column or using Shimadzu LCMS 2020 single quad with Prominence UFLC system with SPD-20 A DAD. Example 1: Synthesis of Compound 1

NH

2 HO

H

2 N \\ N

NH

2 N-O 1 25 Step la: tBuO tBuO OH C 2

H

5 OCOCI/NMM NH 2 BocHN ) BocHN Liq.NH 3 /THF O 1a lb 18 WO 2015/033299 PCT/IB2014/064279 Ethylchloroformate (1.5 g, 13.78 mmol) and N-Methylmorpholine (1.4 g, 13.78 mmol) were added to a solution of compound la (3 g, 11.48 mmol) in TIHF (30 mL) and stirred at -20 'C. After 20 min. Liquid ammonia (0.77 g, 45.92 mmol) was added to the active mixed anhydride formed in-situ and stirred at 0-5 'C for 20 min. The completeness of 5 the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with NaHCO 3 , citric acid, brine solution, dried over Na 2

SO

4 and evaporated under reduced pressure to get 2.9 g of compound lb (Yield: 96.3%). LCMS: 261.0 (M+H)*. 10 Step 1b: tBuO N TFAA tBuO

NH

2 "N BocHN Pyridine BocHN N 0 lb 1c Trifluroacetic anhydride (9.7 g, 46.0 mmol) was added to a solution of compound lb (8 g, 30.7 nunol) in pyridine (24.3 g. 307.0 mnol) and stirred at room temperature for 3 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture 15 was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with NaHCO 3 , citric acid., brine solution, dried over Na 2

SO

4 and evaporated under reduced pressure to afford 7 g of compound Ic (Yield: 94.0%). LCMS: 187.2 (M-'Bu )*. Step ic: tBuO tBuO NH2H.HCI ANH BocHN A K 2 CO3/EtOH BocHN NH 2 N'OH 20 1C id Hydroxylamine hydrochloride (3 g, 43.37 mmol) and potassium carbonate (6 g, 43.37 mmol) were added to a solution of compound Ic (7 g, 28.91 mmol) in EtOH (70 m L) and stirred at 90 'C for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned 25 between water and ethyl acetate. Organic layer was washed with brine solution, dried over Na 2

SO

4 and evaporated under reduced pressure. The crude compound was purified 19 WO 2015/033299 PCT/IB2014/064279 by silica gel column chromatography (Eluent: 0-5% ethyl acetate in hexane) to get 4.2 g of compound Id (Yield: 52.8%). LCMS: 276.4 (M+H). Step Id: 'BuO NHCPh3 NHCPh 3 1. Deoxo-Fluor@/NMM/CH 2

CI

2 O BocHN OH 2. Comp 1d, NaOAc, EtOH FmocHN 0 NHFmoc Ole 5 Deoxo-Fluor@ (1.83 g. 8.3 mnol) was added to a solution of Fmoc-Asn(Trt)-O1-1 (4.5 g, 7.5 mmol) in CH 2 Ci 2 (50 ml) and stirred at 0 'C for 3 h. Then CH 2 Ci 2 was evaporated and triturated with hexane, decanted and evaporated under vacuum to get the corresponding acid fluoride. NMM (1.17 g, 11.6 nmol) and compound ld (1.6 g, 5.8 mmol) in THF were added to the acid fluoride and stirred at room temperature for 12 h. 10 Then TI-F was evaporated and sodium acetate (0.72 g, 8.7 mmol) was added followed by EtOH (50 mL). The reaction mixture was stirred at 90 'C for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with NaIC0 3 , citric acid, brine solution, dried over Na 2

SO

4 and evaporated 15 under reduced pressure, which was further purified by silica gel column chromatography (Eluent: 0-5% ethyl acetate in hexane) to afford 2.8 g of compound le (Yield: 44.4%). LCMS: 836.4 (M+H). Step le: tBuO NHCPh 3 tBuO NHCPh 3 O Et2NH/CH2Cl2 O BocHN N o N BocHN N t N NI- > ' NHFmoc 'O NH 2 le if 20 To compound le (2.3 g '7 nunol) in CH 2 Cl 2 (10 mL) diethylamine (10 mL) was added and the reaction mixture was stirred at room temperature for 30 min. The resulting solution was concentrated in vacuum to get gummy residue. The crude compound was purified by neutral alumina column chromatography (Eluent: 0-50% ethyl acetate in hexane then 0-5% methanol in chloroform) to get 1.4 g of If (Yield: 90 %). LCMS: 25 636.5 (M±Na)*. Step If: 20 WO 2015/033299 PCT/IB2014/064279 BuO 0 NHCPh 3 HO

NH

2 BocHN N

TFA/H

2

CI

2 1W H 2 N -N O NH 2 H N ' 0

NH

2 1f 1 To a solution of compound If (0.45 g) in CH 2 Ci 2 (5 mL), trifluoroacetic acid (5 mL) and catalytic amount of triisopropylsilane were added and stirred for 3 h at room temperature to remove the acid sensitive protecting groups. The resulting solution was concentrated 5 in vacuum to afford 0.29 g of crude compound 1 which was purified using prep-HPLC method described under experimental conditions. 'H NMR (DMSO-d 6 , 400 MHz): 6 2.58 (in, 2H), 3.53 (m, 3H), 3.91 (t, IH), 4.36 (t, 1H), 6.91 (s, 1H), 7.45 (s, IH); 1 3C NMR (DMSO-d 6 , 400 MHz): 6 20.85, 45.71, 50.23, 65.55, 171.03, 171.41, 181.66. LCMS: 216.2 (M+H); HPLC: ta = 13.1 mi. 10 Example 2: Synthesis of Compound 2

NH

2 HO 0 < OH

H

2 N N N OH N-O H H Step 2a: NHCPh 3 0 2 N 0 OtBu NHCPh 3 tBuO HC0hUO Nf)OtBu tBuO O O O'Bu BocBoc N 2BocHN N OtBu

N-

0

NH

2 TEA/THF N-0 H H O if 2a The urea linkage was carried out by the coupling compound If (2.7 g, 4.39 mmol) in 15 THF (30 mL) at room temperature with compound 2b (1.67 g, 4.39 mmol). The coupling was initiated by the addition of TEA (0.9 g, 8.78 mniol) in THF (10 in L) and the resultant mixture was stirred at room temperature. After completion of 20 h, THF was evaporated from the reaction mass, and partitioned between water and ethyl acetate. Organic layer was washed with water., brine, dried over Na 2

SO

4 and evaporated under 20 reduced pressure to get compound 2a, which was further purified by silica gel column chromatography (Eluent: 0-50% ethyl acetate in hexane) to afford 3.46 g of compound 2a (Yield: 92.10%). LCMS 857.4 (M+H)*. Step 2b: 21 WO 2015/033299 PCT/IB2014/064279 NHCPh 3

NH

2 tBuO 0 OtBu TFA/DCM HO O OH BocH N N OtBu H 2 N H H OH N N-0 H H N-0O 00 2 2a To a solution of compound 2a (0.22 g, 0.25 mmol) in CH 2 Cl 2 (5 in L), trifluoroacetic acid (5 mL) and catalytic amount of triisopropylsilane were added and stirred for 3h at room temperature. The resulting solution was concentrated under reduced pressure to 5 obtain 0.35 g of crude compound. The crude solid material was purified using preparative-HPLC method described under experimental conditions. LCMS: 347.1 (M+H)*; HPLC: tR = 12.9 min. Synthesis of compound 2b (NO2-C 6

H

4 -OCO-Thr (OBu)- O'Bu): OtBu 0 2 N t 4-NO 2 Ph-OCOCI ' OtBu

H

2 N Ou Et 3

N/CH

2 Cl 2 N OtBu 0 H 0 2b 10 To the compound I--Ser(tBu)-O'Bu (2 g, 9.2 nmnol) in CH 2 Clb (20 mL), triethylanine (1.39 g. 13.8 mmol) was added and the solution was stirred at room temperature for 5-10 min. To this mixture, solution of 4-Nitrophenyl chloroformate (2.22 g, 11.04 mmol) in

CH

2 CL2 was added and the resultant mixture was stirred at roorn temperature for 30 min. The completion of the reaction was confirmed by TLC analysis. After completion of 15 reaction, reaction mixture was diluted with CH 2 Ci 2 and washed with water and 5.0 M citric acid solution, dried over Na 2

SO

4 and evaporated under reduced pressure to get crude compound 2b, which was further purified by silica gel column chromatography (Eluent: 0-20% ethyl acetate in hexane) to yield 2.1 g (58.9%) of 2b. Example 3: Synthesis of Compound 3

NH

2 HO7 o N1 2

H

2 N NH 20 N-0 The compound was synthesised using similar procedure as depicted in Example 1 (compound 1) and D-amino acids are linked up in reverse order. Boc-D-Thr('Bu)-OH was used in place of Boc-Ser( t Bu)-OH (compound la, Example 1) and Fmoc-D 22 WO 2015/033299 PCT/IB2014/064279 Asn(trt)-OH in place of Fmoc-Asn(trt)-OH to yield 0.15 g crude material of the title compound 3. LCMS: 230.1 (M+H)*. Example 4: Synthesis of Compound 4

NH

2 HO O 0 OH OH

H

2 N ~c H H N-0 5 The compound was synthesised using similar procedure as depicted in Example 2 for synthesising compound 2 using H-Thr('Bu)-O'Bu instead of H-Ser( t Bu)-O'Bu (in synthesis of compound 2b) to yield 0.35 g crude material of the title compound. The crude solid material was purified using preparative IPLC described under experimental conditions. LCMS: 361.2 (M+H)*, HPLC: tR= 12.19 miin. 10 Example 5: Synthesis of Compound 5

NH

2 HO- O O / OH H2N OH H N N --. >'O

H

2 N N-0 H HiI The compound was synthesised using similar procedure as depicted in Example 4 (compound 4) using D-amino acids are linked up in reverse order. Boc-D-Thr('Bu)-OH was used in place of Boc-Ser( t Bu)-OH, Fmoc-D-Asn(trt)-OH in place of Fmoc-Asn(trt) 15 OH and H-D-Ser( t Bu)-O'Bu was used in place of H-Thr('Bu)-O'Bu to yield 0.3 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 361.3 (M+H)*. HPLC: tR = 13.58 rin. Example 6: Synthesis of Compound 6

NH

2 HO O OH

H

2 N N O I H H 20 N-O 0 The compound was synthesised using similar procedure as depicted in Example 2 by using H-Thr('Bu)-OMe instead of H-Ser( t Bu)-OBu (in synthesis of compound 2b) to yield 0.2 g crude material of the title compound. The crude solid material was purified 23 WO 2015/033299 PCT/IB2014/064279 using preparative IIPLC described under experimental conditions. LCMS: 375.1 (M+H)*, HPLC: ta= 11.84 min. Example 7: Synthesis of Compound 7 NH2 HO OH H2N N N NH2 N-O0 5 Step 7a: 0 2 Na OtBu NHCPh, tBuO NHCPh 3 02N ION B tBuO O Co OtBu NH 0 A BocHN BocHN H H N

N-

0

NH

2 TENTHF N-0 H if 7a The compound 7a was synthesised using similar procedure as for compound 2a (Example 2, step 2a) using H-Thr('Bu)-OMe instead of H-Ser( t Bu)-OtBu to get crude material which was further purified by silica gel column chromatography (Eluent: 0-50% 10 ethyl acetate in hexane) to get 2.0 g of compound 7a (Yield: 74 %). LCMS: 829.2 (M+H)*. Step 7b: NHCPh 3 NHCPh 3 BuO 0 u LiOH/THF tBu 0 Ou -1 \N A JN 0"7 N' OH BocHN ON N H N-0 H H 7a 7b To a solution of compound 7a (0.35 g, 4.0 mmol) in THF (5 mL) was added lithium 15 hydroxide (0.026 g, 0.63 mmol) at 0 'C and the mixture was stirred for 2 h at room temperature. The completion of the reaction was confirmed by TLC analysis. THF was evaporated from the reaction mass, and partitioned between water and ethyl acetate. Organic layer was washed with citric acid, brine solution, dried over Na 2

SO

4 and evaporated under reduced pressure to afford 7b, which was further purified by silica gel 20 column chromatography (Eluent: 0-5% methanol in DCM) to get 0.3 g of product 7b (Yield: 86.7%). LCMS 815.2 (M+H)*. Step 7c: 24 WO 2015/033299 PCT/IB2014/064279 NHCPh 3 NH 2 tBuO o 0K Otq u Rink amide/HOBT/ HO o_ OH NoH DIC/DMFOH

NH

2 BN TEA HS H 2 N NHN N- H H 0 7b 7 Compound 7b (0.295 g, 0.39 mmol) was anchored to Rink amide resin (0.7 g, 0.55 mmol/g) using HOBT (0.072 g, 0.54 mmol) and DIC (0.068 g, 0.54 mmol) method in DMF (10 mL). The resin was stirred for 12 h at room temperature. The resin was washed 5 with DCM, DMF and DCM and dried. The target compound was cleaved from the rink amide resin using TFA (5 mL) and catalytic amount of TIPS. The resin was allowed to remain at room temperature for 2 h with occasional stirring. After 2 h, TFA and TIPS were evaporated under nitrogen atmosphere and the resulting residue was washed with diethyl ether to yield 0.1 g crude material of the title compound 7. The crude solid 10 material was purified using preparative HPLC described under experimental conditions. LCMS: 360.0 (M+H)*, HPLC: tR= 13.88 min. Example 8: Synthesis of Compound 8 O OH HO OH

H

2 N N N OH H HI N-OO , The compound was synthesised using similar procedure as depicted in Example 2 15 (compound 2) using Fmoc-Glu(O t Bu)-OH instead of Fmoc-Asn(Trt)-OH to get 0.4 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 362.1 (M+H)*. HPLC: tR = 13.27 min. The compounds in table 3 below were prepared based on the experimental 20 procedures described above. Table 3 Compound Structure LCMS HPLC No. (M+H)* (tR in min.) 9. NH 2 431.1 4.64 OH OH N N N 4 OH H N- H H 25 WO 2015/033299 PCT/IB2014/064279 10. NH 2 375.2 11.13 ,10 0 0 OH N OH

H

2 N N N O N-O H 11.

NH

2 361.2 11.85 HO OH H2N N N OH H OH N-O 0 12. NH 2 361.2 12.38 HO OH

H

2 N N OH N-O 0 13. NH 2 361.2 12.02 HO OH

H

2 N f OH N- O 0 14. NH 2 375.1 11.74 HO OH

H

2 N N N H N-O 0 15. NH 2 361.1 12.41 HO OH

H

2 N N NH N-0 0 16. NH 2 361.1 12.34 HO O O OH

H

2 N N H N-0 0 17. NH 2 361.2 12.62 N OH N-0 0 18. NH 2 361.2 12.87 HO O O OH

-

OH H2N N OH', Iy H H N-O O 26 WO 2015/033299 PCT/IB2014/064279 19. 0 OH 376.1 12.41 HO OH

H

2 N N OH IH H N-0 0 20. 0 NH 2 375.1 12.31 HO- OH

H

2 N N OH N-O H H O 21. 0 NH 2 361.3 13.19 HO OH yN ~ .K OH

H

2 N N N N N-O H H 0 22. 0 NH 2 375.1 12.52 HO- OH N fOH

H

2 N N N N N-C H H 0 23. 0 NH 2 389.2 12.07 HO- 0 OH

H

2 N N OH N-C H H O0 24. OH 362.2 12.78 HO O O OH

H

2 N -r N N OH N-O H H 25. OH 348.2 13.21 HO O O OH

H

2 N N OH N-O H H 0 27 WO 2015/033299 PCT/IB2014/064279 Example 9: Rescue of mouse splenocyte proliferation in the presence of recombinant PD-L1/PD-L2 Recombinant mouse PD-Li (rm-PDL-1, cat no: 1019-B7-100; R&D Systems) were used 5 as the source of PD-Li. Requirement: Mouse splenocytes harvested from 6-8 weeks old C57 BL6 mice; RPMI 1640 (GIBCO, Cat # 11875); DMEM with high glucose (GIBCO, Cat # D6429); Fetal Bovine Serum [Hyclone, Cat # SH30071.03]; Penicillin (10000unit/mL)-Streptomycin(10,000pg/mL) 10 Liquid (GIBCO, Cat # 15140-122); MEM Sodium Pyruvate solution 100mM (100x), Liquid (GIBCO, Cat # 11360); Nonessential amino acid (GIBCO, Cat # 11140); L Glutamine (GIBCO, Cat # 25030); Anti-CD3 antibody (eBiosciences - 16-0032); Anti CD28 antibody (eBiosciences - 16-0281); ACK lysis buffer (1mL) (GIBCO, Cat # A10492); Histopaque (density-1.083 gm/mL) (SIGMA 10831); Trypan blue solution 15 (SIGMA-T8154); 2 mL Norm Ject Luer Lock syringe- (Sigma 2014-12); 40pm nylon cell strainer (BD FALCON 35230); Hemacytometer (Bright line-SIGMA Z359629); FACS Buffer (PBS/0.1% BSA): Phosphate Buffered Saline (PBS) pH 7.2 (HiMedia TS1006) with 0.1% Bovine Serum Albumin (BSA) (SIGMA A7050) and sodium azide (SIGMA 08591); 5 mM stock solution of CFSE: CFSE stock solution was prepared by 20 diluting lyophilized CFSE with 180 pL of Dimethyl sulfoxide (DMSO C 2 HSO, SIGMA-D-5879) and aliquoted in to tubes for further use. Working concentrations were titrated from 10 pM to 1 pM. (eBioscience-650850-85); 0.05% Trypsin and 0.02% EDTA (SIGMA 59417C); 96-well format ELISA plates (Corning CLS3390); BD FACS caliber (E6016); Recombinant mouse B7-H1/PDL1 Fc Chimera, (rm-PD-L1 cat no: 25 1019-B7-100). Protocol Splenocyte preparation and culturing: Splenocytes harvested in a 50 mL falcon tube by mashing mouse spleen in a 40pm cell strainer were further treated with 1 mL ACK lysis buffer for 5 min at room temperature. 30 After washing with 9 mL of RPMI complete media, cells were re-suspended in 3 mL of 1xPBS in a 15 mL tube. 3 mL of Histopaque was added carefully to the bottom of the tube without disturbing overlaying splenocyte suspension. After centrifuging at 800xg for 20 min at room temperature, the opaque layer of splenocytes was collected carefully 28 WO 2015/033299 PCT/IB2014/064279 without disturbing / mixing the layers. Splenocytes were washed twice with cold 1xPBS followed by total cell counting using Trypan Blue exclusion method and used further for cell based assays. Splenocytes were cultured in RPMI complete media (RPMI + 10% fetal bovine 5 serum + ImM sodium pyruvate + 10,000units/mL penicillin and 10,000pg/mL streptomycin) and maintained in a CO 2 incubator with 5% CO 2 at 37 C. CFSE Proliferation assay: CFSE is a dye that passively diffuses into cells and binds to intracellular proteins. 1x106 cells/mL of harvested splenocytes were treated with 5 pM of CFSE in pre-warmed 10 1xPBS/0.1% BSA solution for 10 min at 37 'C. Excess CFSE was quenched using 5 volumes of ice-cold culture media to the cells and incubated on ice for 5 min. CFSE labelled splenocytes were further given three washes with ice cold complete RPMI media. CFSE labelled 1x10 5 splenocytes added to wells containing either MDA-MB231 cells (1x10 5 cells cultured in high glucose DMEM medium) or recombinant human PDL 15 1 (100 ng/mL) and test compounds. Splenocytes were stimulated with anti-mouse CD3 and anti- mouse CD28 antibody (1 pg/mL each), and the culture was further incubated for 72 h at 37 'C with 5% CO 2 . Cells were harvested and washed thrice with ice cold FACS buffer and % proliferation was analysed by flow cytometry with 488 nm excitation and 521 nm emission filters. 20 Data compilation, processing and inference: Percent splenocyte proliferation was analysed using cell quest FACS program and percent rescue of splenocyte proliferation by compound was estimated after deduction of % background proliferation value and normalising to % stimulated splenocyte proliferation (positive control) as 100%. 25 Stimulated splenocytes: Splenocytes + anti-CD3/CD28 stimulation Background proliferation: Splenocytes + anti-CD3/CD28 + PD-Li Compound proliferation: Splenocytes + anti-CD3/CD28 + PD-Li + Compound Compound effect is examined by adding required conc. of compound to anti-CD3/CD28 stimulated splenocytes in presence of ligand (PDL-1) (Table 4). 30 Table 4 29 WO 2015/033299 PCT/IB2014/064279 Percent rescue of Percent rescue of Compound splenocyte Compound splenocyte No. proliferation No. proliferation (@100 nM compound (@100 nM compound concentration) concentration) 1 93 14 75 2 50 15 83 4 89 16 72 5 67.6 17 55 6 84 18 64 7 55 19 88 8 67 20 69 9 34 21 47 10 49 22 55 11 90 23 74 12 64 24 52 13 74 25 91 5 30

Claims (13)

1. A compound of formula (I) R, R, R3 R, HN N R 2 H N Q R4/ wherein, 5 QisSorO; R 1 is side chain of an amino acid Ser or Thr, optionally substituted with alkyl or acyl; R 2 is hydrogen or -CO-Aaa; Aaa is an amino acid residue Thr or Ser; wherein a C-terminus thereof is a free 10 terminus, is amidated or is esterified; R 3 is side chain of an amino acid selected from Asn, Asp, Gln or Glu; ----- is an optional bond; R4 and R 5 independently are hydrogen or absent; R 6 is selected from hydrogen, alkyl or acyl; 15 or a pharmaceutically acceptable salt or a stereoisomer thereof.

2. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (IA): R, R3 0 N H 2 N N Aaa N___ H N-O (IA) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein, 20 R 1 is side chain of an amino acid Ser or Thr, optionally substituted with alkyl or acyl; R 3 is side chain of an amino acid selected from Asn, Asp, Gln or Glu; Aaa is an amino acid residue Thr or Ser; wherein a C-terminus thereof is a free terminus, is amidated or is esterified. 25 3. The compound according to claim 1, wherein the compound of formula (I) is a compound of formula (IB): 31 WO 2015/033299 PCT/IB2014/064279 R1 R 3 N H 2 N NH 2 N-0 (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein, R 1 is side chain of an amino acid Ser or Thr, optionally substituted with alkyl or acyl; 5 R 3 is side chain of an amino acid selected from Asn, Asp, Gln or Glu.

4. The compound according to claim 1, wherein R 1 is side chain of Ser or Thr; R 2 is -CO-Aaa; Aaa is an amino acid residue Thr or Ser; wherein the C-terminus is free; 10 R 3 is side chain of Asn or Glu.

5. The compound according to claim 1, wherein Q is 0.

6. The compound according to claim 1, wherein R 6 is -C(O)CH 3 , -C(O)CH 2 CH 3 , C(O)(CH 2 ) 2 CH 3 , -C(O)(CH 2 ) 3 CH 3 , -C(O)(CH 2 ) 4 CH 3 or -C(O)(CH 2 ) 5 CH 3 .

7. A compound according to claim 1 is selected from the group consisting of Comp Comp ound Structure ound Structure No. No. 1. NH 2

14. NH 2 HO HO _ 0 OH N N OH " NH 2 H 2 N ~ N N HN H 2 N )-l "H N-0 N-O O 2. NH 2 15. NH 2 HO O O OH HO OH H 2 N N HOH H2N N N OH N-O 0 N-0 0 3. NH 2

16. NH 2 H HO N _ _ OH H 2 N N NH 2 H 2 N N N OH N-O N-O 0 32 WO 2015/033299 PCT/IB2014/064279 4 NH 2

17. NH 2 HO o 0 OH HOO OH 'Z 00 N OH H2 N N OH 6. N HH2i9.O H i H N NN N NO - O ON - - H H O N 000 0 5. NH 2

18. NH 2 HO,, O OH HOO 8. 0 OH HO NOH HO KOH HN N OH H2N N OY H H 2 N -- N N -NO HO HN H H N-N-0 0 O. NH 2

20. O H 2 O N 11. NH20N-OH H 2 N N NOH H 2 N N N N N-0 0 Hi H N-O 0 1. NH2 21. 0 NH 2 HO OH HO OH - 0 N _ H N O H H 2 N - N H 2 N N N N O I , H H______________ H H N-O O N-0 0 9. NH0H 22. HN H 2 0 H 0 HJ. f HHOKOH N N 0 N OH N OH H I H H H 2 N H N H N- 0 N-0 H 0 1. NH 2 OH23. HO O NH 2 O N H OH NHIL OH H 2 'N f-T_ N N );H0: Nf O HH H H 2 N I Z N N N-0 N-0 H H 0 10. NH 2

24. O H 2 HO :- 0 .OH HO Y, OH N .KOH N OH H 2 N *- N - N ( H 2 N I ' N N N- H Hi 0 H H 0 1.NH 2

25. H HON o 0 -_OH HO OH-: H 2 Jy N i N N = O H N y N N)N N I H HiiY2 H H N-0 0 N-0 0 n 12. NH225. 03 WO 2015/033299 PCT/IB2014/064279 13. NH 2 HO H2N:y N N J N OH H H N-0 O or a pharmaceutically acceptable salt or a stereoisomer thereof. 8. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient. 5 9. The pharmaceutical composition according to claim 8 further comprising at least one of an anticancer agent, chemotherapy agent, or antiproliferative compound. 10. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament. 11. A compound according to any one of claims 1 to 7, or a pharmaceutically 10 acceptable salt or a stereoisomer thereof, for use as a medicament for the treatment of cancer or infectious disease. 12. The compound for use according to claim 11, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, lung cancer, melanoma, prostate cancer and renal cancer, bone cancer, cancer of the head or neck, pancreatic cancer, skin 15 cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of 20 the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumours of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or 25 ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. 34 WO 2015/033299 PCT/IB2014/064279 13. The compound for use according to claim 11, wherein the cancer is breast cancer, colon cancer, lung cancer, melanoma, prostate cancer and renal cancer. 14. The compound for use according to claim 11, wherein the infectious disease is a bacterial infectious disease, a viral infectious disease or a fungal infectious disease. 35